John C. Marsh

Combination sequential chemotherapy in advanced reticulum cell sarcoma

Based on studies of the chemotherapy of human leukemia and late stage animal neoplasms which may be kinetically analogous to disseminated reticulum cell sarcoma, a therapy program was devised using sequential cyclophosphamide‐vincristine followed by weekly methotrexate‐cytosine arabinoside. Each cycle of therapy consisted of cyclophosphamide 1.5 g/m2 on day 0 and vincristine 1.4 mg/m2 on days 1, 8, and 15; subsequently, 8 weekly doses of IV cytosine arabinoside 300 mg/m2 and oral methotrexate 120 mg/m2 over 24 hours were given followed by “Leucovorin rescue.” Fifteen patients received 3 such cycles with intervening 2‐week recovery periods. Nine patients achieved complete remission, and 6 had a partial response. Median remission duration was 10 months. Median survival from onset of disease was 15+ months and from beginning of therapy was 14+ months. Five of 7 patients who have relapsed are dead. Toxic manifestations included neutropenia below 1000/mm3 in 10 patients; of these, there were recurrent episodes of sepsis in one. Alopecia occurred in 10, and reversible neurotoxicity in 8 patients.

Recurrent corynebacterium equi infection with lymphoma

A patient with malignant lymphoma developed a cavitating pulmonary lesion from which was isolated Corynebacterium equi as well as Streptococcus pneumoniae. C. equi was also cultured from the blood twice, 2 months apart. The infection was controlled initially with ampicillin. The patient had been exposed to horses while receiving immunosuppressive therapy. This is the first published report of septicemia due to this organism and second reported human infection.

Percutaneous Isolated Liver Perfusion for Treatment of Hepatic Malignancy: Preliminary Report

Chemotherapy for primary or metastatic hepatic malignancy is limited by poor tumor response and dose-related systemic toxicity. As an alternative to chemotherapy infusion by vein or by the hepatic artery, the authors have developed a percutaneous technique of isolated liver perfusion that allows the regional delivery of high-dose chemotherapy to the liver with little systemic toxicity. After placement of a hepatic artery infusion catheter, an 18-F double-balloon catheter is placed into the inferior vena cava through the opposite femoral vein. Balloons are inflated above and below the hepatic veins, thus isolating hepatic venous outflow. The effluent passes through fenestrations in the catheter and is pumped through charcoal hemoperfusion filters where the drug is removed. The filtered blood is returned to the patient through the internal jugular vein. Fifteen treatments have been conducted in eight patients in a phase I dose-escalation study with use of 5-fluorouracil (5-FU). While it is premature to assess tumor response to isolated liver perfusion, the data demonstrate that the procedure is safe and is tolerated by patients. Pharmacokinetic studies show a 5-FU extraction of up to 85%, with minimal drug leakage into the systemic circulation. This technique shows potential for improving liver tumor response while decreasing systemic toxicity.

Development of a combination chemotherapy program for adult acute leukemia: CAM and CAM‐L

A combination chemotherapy program for the treatment of adult acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) was devised on the basis of theoretical considerations and experimental evidence that a combination of cell cycle‐nonspecific and cell cycle‐specific agents should be used for induction therapy. The drugs, cyclophosphamide, cytosine arabinoside, and methotrexate, were given as once‐weekly pulses until marrow hypoplasia or remission was attained. Complete marrow remissions were achieved in 7 out of 14 patients with AML and 5 out of 8 patients with ALL. Toxicity from the combination was tolerable, although occasionally severe. The induction program compares favorably with other induction regimens in adult acute leukemia, but the short remissions underscore the need for the design of new approaches to improve maintenance therapy.

A phase II trial of carboplatin (NSC 241240) in advanced prostate cancer, refractory to hormonal therapy

SummaryTwenty-nine patients with metastatic prostate cancer progressing after hormonal therapy (orchiectomy 19, diethylstilbesterol 10) and who had never received cytotoxic therapy were treated with carboplatin. Patients had good clinical performance status (66% PS 0,1) and adequate renal (creatinine < 2.0 mg/dL) and bone marrow function. The standard dose of carboplatin administered was 400 mg/sq m. Seventeen patients received this dose and 12 either 320 mg/sq m or 250 mg/sq m based on reduced renal function or prior radiation. Five patients had bidimensionally measurable disease: one experienced a partial regression of cervical lymph node metastases of 97 days duration. Twenty-four patients had metastatic disease evaluable by clinical status, bone scan and acid phosphatase. In one patient > 50% reduction in number of abnormal areas of bone scan uptake occurred; 3 patients experienced improvement in clinical status; in no patient did an elevated prostate acid phosphatase return to normal. All patients entered on study have progressed and died: median time to progression was 94 days (6 to 625 days); median survival was 297 days (6–1152 days). The primary toxicity of carboplatin was myelosuppression. The median WBC and platelet nadirs after cycle one were 3150/cu mm and 93,000/cu mm, respectively. Dose escalations to grade 2 or greater myelosuppression were mandated. Twenty-six achieved at least grade 2 myelosuppression during carboplatin treatment. We conclude that carboplatin administered at this dose and schedule has no important activity in hormone refractory prostate cancer.

Cyclophosphamide, cytosine arabinoside and methotrexate versus cytosine arabinoside and thioguanine for acute non-lymphocytic leukemia in adults.

One‐hundred and fifty‐one adults with acute non‐lymphocytic leukemia (ANLL) were entered into an Eastern Cooperative Oncology Group protocol (EST‐1473) comparing twice daily cytosine arabinoside and thioguanine (AT) with weekly cyclophosphamide, cytosine arabinoside, and methotrexate (CAM) for remission induction. Of 111 evaluable patients, 16 treated with CAM and 16 treated with AT entered complete remission (CR) on their initial therapy and 5 additional patients entered CR on crossover for a total of 37 or 33% of the evaluable patients. Of the 71 patients who survived three weeks or longer, the overall CR rate was 52%. Cytochemical studies were performed on 85% of the evaluable cases. Minor disagreements between morphologic subtypes of ANLL occurred in 50% of cases. There was no difference in response rates between the major subtypes of ANLL regardless of whether the investigators diagnosis or the cytochemical reference laboratory diagnosis was used. The median survival of all evaluable patients was 4.9 weeks; those patients who responded with a CR had a median survival of 60 weeks, while those who did not have a median survival of <3 weeks. Age <60, ambulatory performance status, or fewer than 50% marrow blasts were also associated with a better response rate and longer survival. CAM had more severe mucositis and vomiting associated with it than did AT, but toxicities were otherwise comparable. Weekly CAM and AT appear to be equally effective regimens in the treatment of ANLL.

IgA Associated Lymphoplasmacytic Tumor Involving the Conjunctiva, Eyelid, and Orbit

A 65-year-old white man had an unusual disseminated lymphoid tumor that first appeared in the subconjunctival tissues of the right eye. The tumor later appeared in the skin, lymph nodes, and left upper eyelid and orbit. A monoclonal serum IgA spike was present although the urine did not contain Bence Jones proteins. The cells of the tumor appeared to be plasmacytoid lymphocytes. Prominent intranuclear inclusions, or Dutcher bodies, were present. Throughtout the 11-year history, the patient has been treated only with local excision and radiation.

Phase II trial of spirogermanium and vindesine in malignant glioma.

Fifty-four adults with recurrent malignant glioma were treated on an Eastern Cooperative Oncology Group (ECOG) trial. All had previous radiation therapy, and 70% had previous chemotherapy. They were assigned to either vindesine 3 mg/m2 weekly or spirogermanium 80 mg/m2 three times weekly with escalation to 120 mg/m2. The response was 4% to vindesine, and 8% to spirogermanium. The duration of response was 53 days for a patient who had clinical improvement only, but >151 days and>1066 days for two patients who had achieved a >50% reduction in tumor size by computed tomography (CT). The toxicities were hematologic for vindesine and neurologic for spirogermanium. Neither agent seems to have sufficient efficacy to warrant further trials in previously treated glioma patients.

Applications of Cell Kinetic Techniques to Human Malignancies

It is the purpose of this chapter to summarize methods that are currently and potentially available to measure the kinetics of cancer cells and to review data that are available for specific human neoplasms. The chapter includes information that influences the planning of treatment as well as information that reflects the response to therapy. A variety of techniques, both in vitro and in vivo, that have been developed in animal tumor systems are now being applied to human neoplasms. Lightdale and Lipkin (1975) reviewed some of these methods in Volume 3 of this series. Although much information on the kinetics of animal tumor systems is available, the extrapolation of such data is often speculative and misleading. Accordingly, we will restrict our discussion to specific information derived from human tumors or methods that are potentially available.

Biochemical modulation of 5-fluorouracil with brequinar: results of a phase I study

Biochemical modulation can increase the efficacy of 5-fluorouracil (5-FU). Pizzorno et al. have previously shown that brequinar, a de novo pyrimidine synthesis inhibitor, enhances the antitumor effect of 5-FU in vivo [Cancer Res 52: 1660–1665, 1992]. On the basis of their data, we conducted a phase I study of brequinar in combination with 5-FU in patients with refractory solid tumors. The initial dose (100 mg/m2) of brequinar was raised in 100-mg/m2 increments in cohorts of three assessable patients. The initial dose of 5-FU was 500 mg/m2, but escalation was allowed in patients who showed no significant toxic reaction. Brequinar was administered over 1 h and 5-FU over 2 h starting 18–20 h after the initiation of infusion of brequinar. Treatments were repeated weekly. Responses were evaluated after 4 weeks (one course) and then every 8 weeks thereafter. Pharmacokinetics of brequinar and determination of plasma uridine levels were performed in at least three patients at each dose level. Of the 25 patients registered in the study, 21 were assessable for toxicity studies. The dose of brequinar was escalated up to 600 mg/m2. In addition, the dose of 5-FU was increased to 600 mg/m2 as a result of a lack of a significant toxic reaction in the first nine patients. No objective responses were observed. One patient developed grade 3 stomatitis, and one developed grade 3 esophagitis at the 400 and 600 mg/m2 dose of brequinar, respectively. Brequinar produced a dosedependent decrease in plasma uridine levels at doses up to 500 mg/m2. No additional decrease in plasma uridine occurred with higher doses of brequinar, thus suggesting a plateau effect. This observation prompted us to terminate the study before reaching the maximum tolerated dose of brequinar. Our data indicate that brequinar in doses≥400 mg/m2 results in significant biochemical modulation. The lack of toxicity seen at these doses of brequinar suggests that the initial dose of the effector agent 5-FU should be increased in future studies.